Signalling via the receptor of advanced glycation end-products (RAGE) although complex and not fully elucidated in the setting of diabetes, is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic (collagen I and IV, fibronectin) and the inflammatory marker, MCP-1 in primary mouse mesangial cells (MC) and in kidney cortex. RNA-seq analysis in MCs from RAGE -/- and wild type mice confirmed these observations...

Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling...

The relationship of MetS (metabolic syndrome) and insulin resistance (one of its key pathophysiological mediators) with diastolic dysfunction and myocardial fibrosis is not well understood. This study aimed to evaluate the association of MetS with diastolic function and myocardial extracellular matrix (ECM) using cardiac magnetic resonance imaging (CMR) in a large community-based population.This cross-sectional analysis included 1,582 participants from the Multi-Ethnic Study of Atherosclerosis with left ventricular ejection fraction ≥50% and no past history of cardiac events...

Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type-2 diabetes (T2D) and linked to peripheral insulin resistance. However, the impact of AcylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1) women with gestational diabetes (GDM) and 2) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D or returned to normoglycemia within a two-year follow-up period...

Mammalian genomes encode a huge number of LncRNAs with unknown functions. This study determined the role and mechanism of a new LncRNA, LncRNA Suppressor of Hepatic Gluconeogenesis and Lipogenesis (LncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and NAFLD patient, the expression levels of mouse LncSHGL and its human homologous LncRNA B4GALT1-AS1 were reduced. Hepatic LncSHGL restoration improved hyperglycemia, insulin resistance and steatosis in obese diabetic mice, whereas hepatic LncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice...

Tight junctions (TJs) involve close apposition of transmembrane proteins between cells. While TJ proteins have been studied in detail, the role of lipids is largely unknown. We addressed the role of very long chain (VLC ≥26) ceramides in TJs using diabetes induced loss of blood-retinal barrier as a model. VLC fatty acids that incorporate into VLC ceramides are produced by elongase ELOVL4. ELOVL4 is significantly reduced in the diabetic retina. Overexpression of ELOVL4 significantly decreased basal permeability, inhibited VEGF and IL-1b induced permeability and prevented VEGF-induced decrease in occludin expression and border staining of TJ proteins; ZO-1 and claudin-5...

Although B cells reactive with islet autoantigens are silenced by tolerance mechanisms in healthy individuals, they can become activated and contribute to development of type 1 diabetes. We previously demonstrated that high-affinity insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment in peripheral blood of healthy subjects. Consistent with their activation early in disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all autoantibody positive pre-diabetic and new-onset type 1 diabetes patients, a time when they are found in pancreatic islets...

The proliferative response of non-β islet endocrine cells in response to type 1 diabetes (T1D) remains undefined. We quantified islet endocrine cell proliferation in a large collection of non-diabetic control and T1D human pancreata across a wide range of ages. Surprisingly, islet endocrine cells with abundant proliferation were present in many adolescent and young adult T1D pancreata. But, the proliferative islet endocrine cells were also present in similar abundance within control samples. We queried the proliferating islet cells with antisera against various islet hormones...

Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main target for alterations in insulin resistant states, the relevance of MAM integrity in muscle insulin resistance is unknown. Deciphering the importance of MAMs on muscle insulin signaling could help to clarify this controversy...

Although central nervous system has been implicated in glucocorticoid-induced fat mass gain, the underlying mechanisms are poorly understood. The aim of our current study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well-known that SGK1 expression is induced by acute glucocorticoid treatment, interestingly, we found its expression was decreased in the arcuate nucleus of the hypothalamus, including POMC neurons, following chronic dexamethasone (Dex) treatment...

The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells (ASC), and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis...

Stress responses promote obesity and insulin resistance, in part, by activating the stress-responsive mitogen-activated protein kinases (MAPKs), p38 MAPK and c-Jun NH2 kinase (JNK). Stress also induces expression of MAPK phosphatase-1 (MKP-1), which inactivates both JNK and p38 MAPK. However, the equilibrium between JNK/p38 MAPK and MKP-1 signaling in the development of obesity and insulin resistance is unclear. Skeletal muscle is a major tissue involved in energy expenditure and glucose metabolism. In skeletal muscle, MKP-1 is upregulated in high fat-diet fed mice and in skeletal muscle of obese humans...